The Journal of Clinical Pharmacology最新文献

{"title":"Assessing the Utility of a Genotype-Guided Tacrolimus Equation in African American Kidney Transplant Recipients: A Single Institution Retrospective Study","authors":"Joy E Obayemi MD,&nbsp;Lauren Callans BA,&nbsp;Nikhil Nair BS, MB,&nbsp;Hui Gao PhD,&nbsp;Divya Gandla BS,&nbsp;Bao-Li Loza PhD,&nbsp;Sarah Gao BA,&nbsp;Maedeh Mohebnasab MD,&nbsp;Jennifer Trofe-Clark PharmD,&nbsp;Pamala Jacobson PharmD,&nbsp;Brendan Keating DPhil","doi":"10.1002/jcph.2461","DOIUrl":"10.1002/jcph.2461","url":null,"abstract":"<p>Tacrolimus metabolism is heavily influenced by the <i>CYP3A5</i> genotype, which varies widely among African Americans (AA). We aimed to assess the performance of a published genotype-informed tacrolimus dosing model in an independent set of adult AA kidney transplant (KTx) recipients. <i>CYP3A5</i> genotypes were obtained for all AA KTx recipients (n = 232) from 2010 to 2019 who met inclusion criteria at a single transplant center in Philadelphia, Pennsylvania, USA. Medical record data were used to calculate predicted tacrolimus clearance using the published AA KTx dosing equation and two modified iterations. Observed and model-predicted trough levels were compared at 3 days, 3 months, and 6 months post-transplant. The mean prediction error at day 3 post-transplant was 3.05 ng/mL, indicating that the model tended to overpredict the tacrolimus trough. This bias improved over time to 1.36 and 0.78 ng/mL at 3 and 6 months post-transplant, respectively. Mean absolute prediction error—a marker of model precision—improved with time to 2.33 ng/mL at 6 months. Limiting genotype data in the model decreased bias and improved precision. The bias and precision of the published model improved over time and were comparable to studies in previous cohorts. The overprediction observed by the published model may represent overfitting to the initial cohort, possibly limiting generalizability.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2461","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure–Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling","authors":"Dhananjay D. Marathe PhD,&nbsp;Petra M. Jauslin PhD,&nbsp;Huub Jan Kleijn PhD,&nbsp;Carolina De Miranda Silva PhD,&nbsp;Anne Chain PhD,&nbsp;Anson K. Abraham PhD,&nbsp;Eunkyung A. Kauh MD,&nbsp;Yanfang Liu MD,&nbsp;Rodolfo F. Perini MD,&nbsp;Dinesh P. de Alwis PhD,&nbsp;Lokesh Jain PhD","doi":"10.1002/jcph.2459","DOIUrl":"10.1002/jcph.2459","url":null,"abstract":"<p>Belzutifan (Welireg, Merck &amp; Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia-inducible factor-2α inhibitor, recently approved in the United States for the treatment of von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other VHL disease-associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL-RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure–response (E-R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression-free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time-to-event analyses. Efficacy E-R was generally flat with non-significant positive trends with exposure. The safety E-R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure-dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit–risk assessment in VHL disease-associated neoplasms using E-R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit–risk profile of belzutifan 120 mg once daily dosing in patients with VHL-RCC for labeling and the overall development program.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying Neural ODEs to Derive a Mechanism-Based Model for Characterizing Maturation-Related Serum Creatinine Dynamics in Preterm Newborns","authors":"Dominic Stefan Bräm MSc,&nbsp;Gilbert Koch PhD,&nbsp;Karel Allegaert MD, PhD,&nbsp;John van den Anker MD, PhD, FCP,&nbsp;Marc Pfister MD, FCP","doi":"10.1002/jcph.2460","DOIUrl":"10.1002/jcph.2460","url":null,"abstract":"<p>Serum creatinine in neonates follows complex dynamics due to maturation processes, most pronounced in the first few weeks of life. The development of a mechanism-based model describing complex dynamics requires high expertise in pharmacometric (PMX) modeling and substantial model development time. A recently published machine learning (ML) approach of low-dimensional neural ordinary differential equations (NODEs) is capable of modeling such data from newborns automatically. However, this efficient data-driven approach in itself does not result in a clinically interpretable model. In this work, an approach to deriving an interpretable model with reasonable PMX-type functions is presented. This “translation” was applied to derive a PMX model for serum creatinine in neonates considering maturation processes and covariates. The developed model was compared to a previously published mechanism-based PMX model whereas both models had similar mechanistic structures. The developed model was then utilized to simulate serum creatinine concentrations in the first few weeks of life considering different covariate values for gestational age and birth weight. The reference serum creatinine values derived from these simulations are consistent with observed serum creatinine values and previously published reference values. Thus, the presented NODE-based ML approach to model complex serum creatinine dynamics in newborns and derive interpretable, mathematical-statistical components similar to those in a conventional PMX model demonstrates a novel, viable approach to facilitate the modeling of complex dynamics in clinical settings and pediatric drug development.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Back Pedaling on Baclofen: Highlighting Concerns Surrounding Baclofen use in Phenibut Withdrawal","authors":"Ryan Feldman PharmD","doi":"10.1002/jcph.2463","DOIUrl":"10.1002/jcph.2463","url":null,"abstract":"&lt;p&gt;To the Editor:&lt;/p&gt;&lt;p&gt;I applaud Drs. Penzak and Bulloch for attempting to organize the sparse phenibut literature into usable clinical information.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, some case information reported within this article requires correction. Additionally, important considerations for baclofen use in withdrawal need to be emphasized.&lt;/p&gt;&lt;p&gt;In the authors' discussion of baclofen use for withdrawal, they state: “This approach has been questioned, especially in patients who may be at risk of seizures. Fortunately, there were no reported seizures in any of the published cases after baclofen initiation.”&lt;/p&gt;&lt;p&gt;This statement is incorrect. It cites a case report, published by our author group, in which a patient has a seizure after being sent home on baclofen for phenibut withdrawal.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Later in the discussion, they do accurately describe our case report, contradicting their own statement.&lt;/p&gt;&lt;p&gt;Next, in the authors' discussion of pharmacotherapy for withdrawal management they comment in table 1 that baclofen “Has been used successfully alone and in combination (usually with a benzodiazepine) for the treatment of phenibut withdrawal.” However, withdrawal management entails various strategies. Some patients may taper from phenibut, while others will undergo abstinence, the two may require different treatment strategies. Those undergoing abstinence may experience more severe acute withdrawal syndromes. In our review, 100% of patients undergoing abstinence were managed inpatient and nearly all required multiple medications to stabilize symptoms.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The monotherapy use of baclofens in the published literature has only been for aiding a phenibut taper, or after the acute stabilization phase in abstinence (e.g., maintenance).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The phrasing in this table could be interpreted to suggest baclofen as a monotherapy for patients admitted to handle acute withdrawal during the initial phases of abstinence. Given the risk for severe outcomes in these patients (seizure in 9.1%, intubation in 27.7%), it is important to point out baclofen has no data to support its use as a single agent in this setting.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Finally, the authors discuss baclofen dosing and highlight a previously suggested dosing regimen of 8-10 mg of baclofen per 1 g of phenibut. This recommendation stems from a single case with no comparator.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Every other case report, which utilized baclofen successfully, is just as valid. The only difference is that these authors proposed a dosing strategy in their text. Despite a total lack of scientific rationale, it has unfortunately become a prevalent discussion point in other texts. This suggested dosing implies baclofen is 100 times more potent than phenibut. However, in vitro data demonstrates baclofen has a 28-fold higher affinity for the gamma amino butyric acid-B receptor than phenibut.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Many patients in t","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants","authors":"Yinhua Li PhD,&nbsp;Akifumi Okayama MS,&nbsp;Toshiaki Hagi MS,&nbsp;Chieko Muto PhD,&nbsp;Susan Raber PharmD, MPH,&nbsp;Masahito Nagashima BS","doi":"10.1002/jcph.2454","DOIUrl":"10.1002/jcph.2454","url":null,"abstract":"<p>An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to C_max (t_max) of 48 h post-dose. After the achievement of C_max, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUC_inf and C_max were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity","authors":"Koen P. van Rhee PharmD,&nbsp;Roger J.M. Brüggemann PharmD, PhD,&nbsp;Jason A. Roberts PharmD, PhD,&nbsp;Fredrik Sjövall MD, PhD,&nbsp;Reinier M. van Hest PharmD, PhD,&nbsp;Paul W.G. Elbers MD, PhD,&nbsp;Alan Abdulla PharmD, PhD,&nbsp;Paul D. van der Linden PharmD, PhD,&nbsp;Catherijne A.J. Knibbe PharmD, PhD","doi":"10.1002/jcph.2450","DOIUrl":"10.1002/jcph.2450","url":null,"abstract":"<p>Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI &gt;30 kg/m²) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC &gt;125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (<i>P</i> &lt; .001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI &gt;60 mL/min/1.73 m² may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2450","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women","authors":"Priska Kaufmann PhD,&nbsp;Clemens Muehlan PhD,&nbsp;Marion Anliker-Ort PhD,&nbsp;Giancarlo Sabattini MSc,&nbsp;Nicholas Siebers MD,&nbsp;Jasper Dingemanse PhD","doi":"10.1002/jcph.2455","DOIUrl":"10.1002/jcph.2455","url":null,"abstract":"<p>The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post-marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects.</p><p>This single-center, open-label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre-dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated.</p><p>All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies.</p><p>Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guiding Dyslipidemia Treatment: A Population Pharmacokinetic–Pharmacodynamic Framework for Obicetrapib","authors":"Allison Dunn PharmD, MS,&nbsp;Marc Ditmarsch MD,&nbsp;John J. P. Kastelein MD, PhD,&nbsp;Douglas Kling BS,&nbsp;Annie Neild PhD,&nbsp;Michael H. Davidson MD,&nbsp;Joga Gobburu PhD","doi":"10.1002/jcph.2448","DOIUrl":"10.1002/jcph.2448","url":null,"abstract":"<p>Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3-compartment model with 4-compartment transit absorption and first-order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. The maximum stimulatory effect of obicetrapib on LDL-C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL-C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL-C and HDL-C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision-making throughout the development lifecycle.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Sertraline in Psychiatric and Substance Use Disorders","authors":"Cinthya Eloisa Chávez Castillo MSc,&nbsp;Susanna Edith Medellín Garibay PhD,&nbsp;Rosa del Carmen Milán Segovia PhD,&nbsp;Sergio Zarazúa Guzmán PhD,&nbsp;Helgi Jung Cook PhD,&nbsp;Marisol Orocio Contreras MD,&nbsp;Silvia Romano Moreno PhD","doi":"10.1002/jcph.2457","DOIUrl":"10.1002/jcph.2457","url":null,"abstract":"<p>This study aimed to characterize the population pharmacokinetics of sertraline in Mexican patients with psychiatric and substance use disorders. Fifty-nine patients (13 to 76 years old) treated with doses of sertraline between 12.5 and 100 mg/day were included. Plasma sertraline concentrations were determined in blood samples and five of the main substances of abuse were determined by rapid tests in urine samples. Demographic, clinical, and pharmacogenetic factors were also evaluated. Population pharmacokinetic analysis was performed using NONMEM software with first-order conditional estimation method. A one-compartment model with proportional residual error adequately described the sertraline concentrations versus time. CYP2D6*2 polymorphism and CYP2C19 phenotypes significantly influenced sertraline clearance, which had a population mean value of 66 L/h in the final model. The absorption constant and volume of distribution were fixed at 0.855 1/h and 20.2 L/kg, respectively. The model explained 11.3% of the interindividual variability in sertraline clearance. The presence of the CYP2D6*2 polymorphism caused a 23.1% decrease in sertraline clearance, whereas patients with intermediate and poor phenotype of CYP2C19 showed 19.06% and 48.26% decreases in sertraline clearance, respectively. The model was internally validated by bootstrap and visual predictive check. Finally, stochastic simulations were performed to propose dosing regimens to achieve therapeutic levels that contribute to improving treatment response.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food Effect in Pediatric Populations: Current Practice, Challenges, and Future Potential for Use of Physiologically Based Biopharmaceutics Modeling","authors":"Neil Parrott MSc","doi":"10.1002/jcph.2456","DOIUrl":"10.1002/jcph.2456","url":null,"abstract":"<p>In drug development, the effects of food on oral pharmacokinetics are usually assessed by performing a clinical study in adults where a single dose of the drug is given in a crossover design, and pharmacokinetic parameters derived after dosing in the fasted state are statistically compared to those obtained after a high-calorie meal.<span>¹</span> When it comes to children, ethical concerns limit the conduct of such studies and current regulatory guidance recommends that new pediatric formulations should be assessed for their food effect in adults to guide dosing in children.<span>¹</span> However, the validity of this practice can be questioned. For instance, food effects might differ between children and adults because many of the determining physiological factors, such as stomach volume, gastrointestinal pH, gastric emptying time, intestinal bile salt concentrations, and liver blood flow are age-dependent.<span>^{2, 3}</span> Furthermore, meal types and feeding patterns in children are quite different from those in adults, and the high-fat and high-calorie meal used in adult food effect studies can be inappropriate to project effects in young children. For example, a study was performed where adults were dosed with pediatric formulations of paracetamol and ibuprofen in fasted and fed states in a crossover design.<span>⁴</span> In one arm, the fed state was represented by a 990 kcal standard adult meal whereas an infant 520 kcal formula meal was used in a second arm. Quite distinct fed-state pharmacokinetic profiles were seen for these different meal types. Although the extent of absorption was comparable, the pediatric meal caused slower absorption than the standard adult meal showing that, even for BCS1 drugs, the impact of the meal type should be considered and a pediatric meal may result in different absorption. Further doubts on the validity of the direct transfer of food effects between adults and children were raised by clinical food effects collected for a set of antibiotic suspensions.<span>⁴</span> Only one out of seven drugs shows a food effect that is qualitatively similar in adults and children (Table 1).</p><p>Additional evidence that the current approach for the prediction of pediatric food effects is not optimal was provided in a recent report from Tunehag and colleagues at the FDA.<span>⁵</span> They analyzed pediatric drug development studies submitted from 2012 to 2022. In that 10-year period, 102 drug products were approved for use in children &lt;6, and 43 drug labels give dosing recommendations regarding food directly transferred from adult findings. Fourteen products are recommended to be taken without food in infants aged less than 2, which is problematic considering that children of this age feed more frequently than adults, typically every 2–3 h, and tend to remain in a semi-fed state. On the other hand, for the drug products that were recommended to be ","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2456","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}